Glutamate and gamma-aminobutryic acid (GABA) are major central nervous system (CNS) excitatory and inhibitory neurotransmitters respectively. Selective glutamate release inhibitors (GRIs) appear to be effective treatments for disorders including seizures, amyotrophic lateral sclerosis, and bipolar disorder. Understanding the cellular underpinnings of the acute actions of GRIs on glutamate release is the goal of this proposal. While several glutamate release inhibitors (GRIs) have been described, the evidence for a selective anti-glutamate effect is indirect and has been disputed. Our recent results suggest that the selective anti-glutamate effect of these drugs can be explained by partial block of the presynaptic sodium channels (NaChs) that underlie the action potential. Elucidation of the mechanisms by which partial NaCh block depresses glutamate release should yield insight into the details of action potential coupling to transmitter release and permit more rational and effective drug design. The first aims of the proposal are to understand the acute effects of weak NaCh blockade on glutamate release. NaCh block may disturb action potential coupling to glutamate release either by promoting failure of action potential propagation through branches of the axon or by altering the amplitude of the action potential. Using two in vitro systems for analyzing glutamate neurotransmission, we will distinguish between these two potential mechanisms. Because of the exquisite sensitivity of glutamate release to partial NaCh block, a second hypothesis to be tested is that NaCh inactivation during high-frequency presynaptic activity yields depression of glutamate release, even in the absence of exogenous NaCh blockers. A final aim is to understand the effect of these drugs on recently described postsynaptic amplification of synaptic potentials through atypical non-inactivating sodium channels. Our studies should lend insight into the cellular mechanisms of a class of clinically important anticonvulsants and neuroprotectants. In addition, we expect our results to elucidate details of the mechanisms of action potential coupling to chemical neurotransmission and a possible mechanism of synaptic plasticity.